Structural and Functional Constraints Limit Options for Cytotoxic T-Lymphocyte Escape in the Immunodominant HLA-B27-Restricted Epitope in Human Immunodeficiency Virus Type 1 Capsid

Abstract

Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8؉ cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK 263-272 ) in p24/Gag. Viral escape in KK10 typically occurs through development of an R 264 K substitution in conjunction with the upstream compensatory mutation S 173 A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R 264 have been observed, but factors dictating the preferential selection of R 264 K remain unclear. Here we illustrate that while all observed R 264 mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R 264 K. Importantly, however, none of these mutants replicated as well as an R 264 K variant containing the compensatory mutation S 173 A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R 264 K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R 264 K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R 264 K is due primarily to the ability of the S 173 Acompensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

“…Gag protein was chosen because CTL responses to Gag, particularly to its proteolytic processing product p24 Gag , have been associated with better control of HIV viremia (19,23,(26)(27)(28)(29)(30)(31). Similarly, a direct correlation between Gag-specific T cell responses prior to infection and control of acute viremia was found in DNA-vaccinated macaques (32).…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…First, during HIV and hepatitis C virus (HCV) infections, viral escape from HLA-B27-restricted cytotoxic T cells targeting immunodominant epitopes is undoubtedly a difficult process. It usually requires multiple compensatory mutations to counterbalance structural and functional constraints having a high cost for the viral fitness [48,52,53]. Secondly, a number of immunological benefits of the virus-specific, HLA-B27-restricted CD8…”

The Dynamics of HIV-1 Adaptation in Early Infection

“…These double mutants would take longer to arise than single beneficial mutants. Fitness interactions of this type, more generally known as fitness epistasis, are common and strong in HIV-1 in the context of its adaptation to an alternative host-cell coreceptor (Da Silva et al 2010) and have been reported for the evolution of escape mutants in response to CD8 + T cell selection (Yeh et al 2006;Schneidewind et al 2008).…”